Warning

Fixed Combinations

If using efavirenz/emtricitabine/tenofovir DF (Atripla), consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs) in conjunction with other antiretrovirals.232

If using efavirenz/emtricitabine/tenofovir DF (Atripla), consider that severe, acute exacerbations of HBV have been reported following discontinuance of emtricitabine or tenofovir DF in HIV-infected patients coinfected with HBV.232 The fixed combination is not labeled by FDA for treatment of chronic HBV infection; safety and efficacy not established in HIV-infected patients coinfected with HBV.232 Monitor hepatic function closely with both clinical and laboratory follow-up for at least several months after the fixed combination is discontinued in coinfected patients.232 If appropriate, initiation of HBV treatment may be warranted.232

Introduction

Uses for Efavirenz

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥3 months of age weighing ≥3.5 kg;12101112200201 usually used in conjunction with 2 NRTIs.1

For initial treatment in antiretroviral-naive adults and adolescents, experts state that efavirenz in conjunction with tenofovir alafenamide and emtricitabine or efavirenz in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) are alternative NNRTI-based regimens.200 Efavirenz in conjunction with abacavir and lamivudine (or emtricitabine) is another NNRTI-based regimen option for initial treatment in adults and adolescents when recommended or alternative regimens cannot be used, but use only in those with baseline plasma HIV RNA levels <100,000 copies/mL who are human leukocyte antigen (HLA)-B*5701 negative.200

For initial treatment in antiretroviral-naive pediatric patients, experts state that efavirenz and 2 NRTIs is a preferred regimen for initial treatment in children ≥3 to <12 years of age and an alternative regimen for initial treatment in adolescents ≥12 years of age who are not sexually mature.201 Efavirenz is not recommended for initial treatment in those 3 months to <3 years of age.201

Usually avoid efavirenz in pregnant women during first trimester;1 avoid in women of childbearing age who may become pregnant.1202 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Efavirenz/emtricitabine/tenofovir DF fixed combination (Atripla) can be used in adults, adolescents, and children ≥12 years of age weighing ≥40 kg to decrease pill burden and improve adherence;232 used alone as a complete treatment regimen or used in conjunction with other antiretrovirals.232

USPHS recommends 3-drug regimen of raltegravir in conjunction with emtricitabine and tenofovir DF as the preferred regimen for PEP following occupational exposures to HIV.199 Efavirenz and 2 NRTIs can be considered an alternative regimen, but use for PEP only with expert consultation.199 Preferred dual NRTI option for PEP regimens is emtricitabine and tenofovir DF (may be given as emtricitabine/tenofovir DF; Truvada); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be given as lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.199

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible.199 Do not delay initiation of PEP while waiting for expert consultation.199

Postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as emtricitabine/tenofovir DF; Truvada);198 recommended alternative in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada).198

CDC states efavirenz is an alternative antiretroviral that can be used in nPEP regimens, but use in such regimens only with expert consultation.198

Consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) if nPEP indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if considering a regimen not included in CDC guidelines, source virus is known or likely to be resistant to antiretrovirals, or healthcare provider is inexperienced in prescribing antiretrovirals.198 Do not delay initiation of nPEP while waiting for expert consultation.198

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use alone as a complete treatment regimen or use in conjunction with other antiretrovirals.232 Because antiretrovirals in the fixed combination also are available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if used in conjunction with other antiretrovirals.232 (See Use of Fixed Combinations under Cautions.)

Do not use single-entity efavirenz (Sustiva) and efavirenz/emtricitabine/tenofovir DF (Atripla) concomitantly, unless needed for adjustment of efavirenz dosage (e.g., when fixed combination used concomitantly with rifampin).1232

Capsules (Sustiva)

For adults and pediatric patients ≥3 months of age not able to swallow capsules or tablets, administer capsule contents by mixing with small amount (1–2 teaspoonfuls) of soft food (capsule sprinkle method).1 Consider mixing with infant formula only if infant cannot consume solid foods.1 Administer efavirenz mixture within 30 minutes after preparation; do not consume any additional food or infant formula for 2 hours after the mixture.1

Mixing capsule contents into food: Add 1–2 teaspoonfuls of age-appropriate soft food (e.g., applesauce, grape jelly, yogurt) to a small container.1 Hold appropriate number of capsules (see Table 1) horizontally over the small container, twist open, and empty onto the food.1 Gently mix with a spoon; feed entire mixture to patient.1 Then, add additional 2 teaspoonfuls of soft food to the small container, stir to disperse remaining efavirenz residue, and feed to patient.1

Oral

Efavirenz (Sustiva): 600 mg once daily.199 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Efavirenz (Sustiva): Dosage adjustments not needed in patients with mild hepatic impairment;1 do not use in those with moderate or severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use usual dosage in patients with mild hepatic impairment; however, caution advised.232 Do not use in those with moderate or severe hepatic impairment.232

Renal Impairment

Treatment of HIV Infection

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use usual dosage in patients with Clcr ≥50 mL/minute;232 do not use in those with Clcr <50 mL/minute.232

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1232

Cautions for Efavirenz

Contraindications

Efavirenz and efavirenz/emtricitabine/tenofovir DF: History of clinically important hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic skin eruption) to efavirenz or any ingredient in the formulation.1232

Efavirenz/emtricitabine/tenofovir DF: Consider contraindications associated with each drug in the fixed combination.232

Warnings/Precautions

Interactions

Efavirenz plasma concentrations may be altered if CYP3A substrates, inhibitors, or inducers used concomitantly.1 In addition, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or 2B6.1 (See Interactions.)

Psychiatric Symptoms

Depression, anxiety, and nervousness also reported in clinical studies.1 Although causal relationship not established, there have been occasional postmarketing reports of delusions, psychosis-like behavior, catatonia, and death by suicide in patients receiving efavirenz.1 Aggressive reactions,1 agitation,1 emotional lability,1 mania,1 neurosis,1 and paranoia1 also reported during postmarketing surveillance.

Factors associated with increased occurrence of psychiatric symptoms include history of injection drug use, history of psychiatric disorders, and treatment with antipsychotic drugs at study entry.1232

If serious psychiatric adverse events occur, evaluate to determine if symptoms are related to efavirenz; if so, determine whether risks of continued efavirenz outweigh benefits.1232

Nervous System Effects

Dizziness or insomnia reported frequently; abnormal dreams, hallucinations, or impaired concentration also reported.1 These adverse effects generally begin during first 1–2 days of therapy, improve with continued therapy, and usually resolve after first 2–4 weeks.1

Seizures reported,1 generally in those with a history of seizures.1 Use with caution in patients with history of seizures.1 Monitor anticonvulsant plasma concentrations if used in patients receiving anticonvulsants that are metabolized principally by the liver (e.g., phenytoin, phenobarbital).1 (See Specific Drugs and Laboratory Tests under Interactions.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm if administered during first trimester of pregnancy.1232 Teratogenicity demonstrated in animals.1 Birth defects (including neural tube defects) reported in humans, usually with first-trimester exposure.1 (See Pregnancy under Cautions.)

Advise women of childbearing potential about the teratogenic potential of efavirenz;1232 perform test to rule out pregnancy before initiating efavirenz or fixed combination containing efavirenz.1232

Avoid pregnancy during therapy and for 12 weeks after discontinuance of efavirenz or fixed combination containing efavirenz.1232 Women of childbearing potential should use a reliable method of barrier contraception in addition to or instead of a hormonal contraceptive (oral or other hormonal contraceptive).1200202232 (See Specific Drugs and Laboratory Tests under Interactions.)

Median time to rash onset 11 days in adults and 28 days in pediatric patients; median duration 16 days.1 Mild to moderate rash generally resolves within 1 month with continued efavirenz.1 May be reinitiated after temporary interruption for rash.1 Antihistamines and/or corticosteroids may improve tolerability and hasten resolution of rash.1

Hepatotoxicity

Hepatic failure and hepatitis reported, some with a fulminant course requiring transplantation or resulting in death.1 Hepatic failure has occurred in some patients with no preexisting hepatic disease or other identifiable risk factors.1

Use with caution in patients with hepatic impairment.1232 (See Hepatic Impairment under Cautions.)

Do not use efavirenz/emtricitabine/tenofovir DF concomitantly with single-entity efavirenz, unless needed for adjustment of efavirenz dosage (e.g., when fixed combination used concomitantly with rifampin).1232 (See Specific Drugs and Laboratory Tests under Interactions.)

Because the antiretrovirals contained in efavirenz/emtricitabine/tenofovir DF also are available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if the fixed combination is used in conjunction with other antiretrovirals.232

Do not use efavirenz/emtricitabine/tenofovir DF concomitantly with any preparation containing emtricitabine or tenofovir DF.232 In addition, do not use concomitantly with any preparation containing lamivudine or with adefovir.232

Cardiovascular and Lipid Effects

Prolongation of QT interval corrected for rate (QTc) reported.1 Consider alternative antiretroviral in patients at increased risk of torsades de pointes and in those receiving a drug known to increase risk of torsades de pointes.1 (See Interactions.)

Increased serum concentrations of total cholesterol and triglycerides reported.1 Assess serum cholesterol and triglycerides prior to and periodically during therapy.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported in the setting of immune reconstitution;1 time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1

Specific Populations

Pregnancy

Efavirenz may cause fetal harm if administered during first trimester of pregnancy.1232 There are retrospective case reports of neural tube defects in infants born to mothers with first trimester exposure to efavirenz,1 but prospective pregnancy data not sufficient to adequately assess this risk.1202

Data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall birth defects for efavirenz compared with background rate for birth defects.1

Women of childbearing potential should use effective contraceptive measures during therapy and for 12 weeks after discontinuance of efavirenz or efavirenz/emtricitabine/tenofovir DF.1232 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Experts state efavirenz in conjunction with 2 NRTIs is an alternative NNRTI-based regimen for initial treatment in antiretroviral-naive pregnant women,202 but may be a preferred NNRTI-based regimen for initial treatment when drug interactions with PI-based regimens are a concern or when the convenience of a fixed-combination, single-tablet, once-daily regimen is advantageous.202 However, these experts state efavirenz should be avoided during first 8 weeks of pregnancy.202

Experts also state that antiretroviral regimens that do not include efavirenz should be strongly considered in women who are planning to become pregnant or are sexually active and not using effective contraception, provided such regimens are acceptable to the provider and not expected to compromise the health of the woman.202

If a pregnant woman already receiving an efavirenz-containing regimen presents for antenatal care during first trimester, some experts suggest the regimen can be continued if well tolerated and providing adequate virologic suppression.202 This strategy recognizes that risk of neural tube defects is limited to first 5–6 weeks of pregnancy and pregnancy rarely recognized until after 4–6 weeks and that unnecessary changes in antiretroviral regimens during pregnancy may be associated with loss of virologic control and increased risk of perinatal HIV transmission.202

If efavirenz or a fixed combination containing efavirenz is used during first trimester or if pregnancy occurs, apprise patient of potential harm to the fetus.1232

Lactation

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1202232

Pediatric Use

Efavirenz (Sustiva): Safety and efficacy not evaluated in neonates and infants <3 months of age or who weigh <3.5 kg;1 not recommended in these pediatric patients.1201 Some experts state efavirenz not recommended for initial treatment in antiretroviral-naive pediatric patients 3 months to <3 years of age.201

Efavirenz/emtricitabine/tenofovir DF (Atripla): Safety and efficacy not established in pediatric patients <12 years of age or weighing <40 kg.232

Adverse effects reported with efavirenz in pediatric patients 3 months to 21 years of age are similar to those reported in adults with the exception of rash.1 Rash reported more frequently in children than adults and the incidence of moderate to severe rash has been greater in children than adults.1

Not recommended in sexually active adolescent females of childbearing potential who desire to become pregnant or when reliable contraception cannot be ensured.201 (See Pregnancy under Cautions.)

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1232

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1232

Hepatic Impairment

Efavirenz (Sustiva): Use with caution in mild hepatic impairment;1 do not use in moderate or severe hepatic impairment.1

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use with caution in mild hepatic impairment;232 do not use in moderate or severe hepatic impairment.232

Monitor hepatic enzyme concentrations in patients with known or suspected HBV or HCV infection, patients with substantially increased transaminase concentrations, and in patients receiving other drugs associated with hepatotoxicity.1 (See Hepatotoxicity under Cautions.)

Renal Impairment

Efavirenz (Sustiva): Pharmacokinetics not specifically studied; clinically important decreases in clearance not anticipated.1 (See Renal Impairment under Dosage and Administration.)

Efavirenz/emtricitabine/tenofovir DF (Atripla): Do not use in those with Clcr <50 mL/minute.232

Interactions for Efavirenz

The following drug interactions are based on studies using efavirenz.1 Drug interaction studies not performed using efavirenz/emtricitabine/tenofovir DF.232 When fixed combinations are used, consider interactions associated with each drug in the fixed combination.232

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP isoenzymes 3A, 2B6, 2C9, or 2C19 with possible alteration in metabolism of efavirenz and/or other drug.1

Carbamazepine: Data insufficient to make dosage recommendations for concomitant use with efavirenz;1 use with caution and monitor anticonvulsant concentrations;1200 consider alternative anticonvulsant200

Phenobarbital, phenytoin: Use caution and monitor anticonvulsant concentrations if used with efavirenz;1200 consider alternative anticonvulsant200

Efavirenz/emtricitabine/tenofovir DF: Data insufficient to make dosage recommendations for concomitant use with carbamazepine;232 use alternative anticonvulsant232

Rifabutin: Manufacturer of efavirenz states increase daily rifabutin dosage by 50% and consider doubling rifabutin dosage when given 2 or 3 times weekly; experts suggest increase rifabutin dosage to 450–600 mg once daily or 600 mg 3 times weekly, provided regimen does not include a PI1200

Rifampin: Manufacturer states increase efavirenz dosage to 800 mg once daily in those weighing ≥50 kg;1 experts recommend efavirenz 600 mg once daily for patients weighing <60 kg and efavirenz 800 mg once daily in those weighing >60 kg and state virologic response should be monitored and therapeutic drug monitoring considered;200 if using efavirenz/emtricitabine/tenofovir DF, use 1 tablet of fixed combination (see Preparations) and 200 mg of single-entity efavirenz once daily to provide efavirenz dosage of 800 mg daily232

Hormonal contraceptives (oral or other hormonal contraceptives): Use a barrier contraceptive as an alternative to or in addition to hormonal contraceptive in women of childbearing potential during and for 12 weeks after efavirenz therapy is discontinued1200202

Substantially decreased concentrations of amprenavir (active metabolite of fosamprenavir) if used with fosamprenavir (without low-dose ritonavir);1205 additional pharmacokinetic interactions if used with ritonavir-boosted fosamprenavir205

Cyclosporine, sirolimus, tacrolimus: Dosage of immunosuppressive agent may need to be adjusted if used with efavirenz or efavirenz/emtricitabine/tenofovir DF;1232 whenever efavirenz or efavirenz/emtricitabine/tenofovir DF is initiated or discontinued, monitor immunosuppressive agent concentrations for at least 2 weeks until stable1232

Indinavir

Decreased indinavir AUC; no clinically important effect on efavirenz concentrations or AUC1

Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): clinically important pharmacokinetic interactions with efavirenz not expected;181 if used with efavirenz/emtricitabine/tenofovir DF, decreased ledipasvir concentrations but no clinically important effect on sofosbuvir or efavirenz concentrations181200

Ledipasvir/sofosbuvir: Dosage adjustments not needed if used with efavirenz;181200 if used with efavirenz/emtricitabine/tenofovir DF, monitor for tenofovir-associated adverse effects232

Efavirenz/emtricitabine/tenofovir DF): No clinically important effect on pharmacokinetics of sofosbuvir, efavirenz, or emtricitabine;176 decreased velpatasvir concentrations and AUC and increased tenofovir concentrations and AUC176

Compared with administration in the fasting state, AUC increased 28% when a single 600-mg efavirenz dose as tablets was administered with a high-fat, high-calorie meal (1000 kcal, 500–600 kcal from fat).1

Tablets

Actions and Spectrum

Pharmacologically related to other NNRTIs (e.g., delavirdine, etravirine, nevirapine, rilpivirine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.123612145253212215

Inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.13

HIV-1 with reduced susceptibility to efavirenz have been selected in vitro and have emerged during therapy with the drug.139141818

Strains of HIV-1 resistant to efavirenz may be cross-resistant to some other NNRTIs (e.g., delavirdine, nevirapine).39101832502002011215

Cross-resistance between efavirenz and NRTIs unlikely since the drugs bind at difference sites on reverse transcriptase and have difference mechanisms of action.1391032 Cross-resistance between efavirenz and PIs unlikely since the drugs have different target enzymes and mechanisms of action.132

Advice to Patients

Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1232 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1232

Importance of using efavirenz in conjunction with other antiretrovirals—not for monotherapy.1 Efavirenz/emtricitabine/tenofovir DF (Atripla) can be used alone as a complete treatment regimen or can be used in conjunction with other antiretrovirals.232

Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1232

Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1200

Importance of reading patient information provided by the manufacturer.1232

Importance of taking efavirenz on an empty stomach, preferably at bedtime.1232

In patients not able to swallow capsules or tablets, importance of patient or caregiver reading and carefully following instructions for mixing and administering capsule contents in small amount of soft food or infant formula.1

If a dose is missed, patient should take the missed dose as soon as it is remembered, unless it is almost time for next dose.1 If a dose is missed, do not take a double dose to make up for missed dose.1

Advise patients that adverse CNS effects (e.g., dizziness, insomnia, impaired concentration, drowsiness, abnormal dreams) are common during first weeks of efavirenz therapy.1232 Taking the drug at bedtime may improve tolerability.1 Additive effects may occur if used with alcohol or psychoactive drugs.1232 If CNS effects occur, avoid potentially hazardous tasks such as driving or operating machinery.1232

Risk of rash.1232 Since rash may be serious, importance of promptly contacting clinician if rash occurs.1232

Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1232

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.1232

Importance of women using a reliable barrier method of contraception instead of or in addition to a hormonal contraceptive (oral or other hormonal contraceptive) during and for 12 weeks after efavirenz therapy.1232

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1232 Advise HIV-infected women not to breast-feed.1232

Importance of advising patients of other important precautionary information.1232 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

61. Centers for Disease Control and Prevention. Notice to readers: updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR Recomm Rep. 2000; 49:185-9.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (July 14, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (April 26, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (October 26, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov